The selective introduction of fluorine atoms into organic molecules is of great interest, due to the broad applications of fluorine-containing compounds in pharmaceutical and agricultural chemistry, and material science.1 Recently, two classes of gem-difluoro compounds have attracted much attention: 1,1-difluoro-1-alkenes and difluoromethylalkanes.2 1,1-Difluoro-1-alkene functionality has been known to act as a bioisostere for aldehydes and ketones,3 and it is critical to many biologically active molecules such as enzyme inhibitors,4 and pesticides.5 1,1-Difluoro-1-alkenes are also useful synthetic precursors for the preparation of many other fluorinated compounds and polymers.6 A number of examples of the preparation of 1,1-difluoro-1-alkenes have been documented in the literature, mostly relying on the addition of a reagent that adds the terminal carbon or the terminal two or three carbons containing the two fluorines to an electrophile or a nucleophile.2a,6-8 The most common method is the Wittig reaction using difluoromethylene ylides.7 However, these methods either need specialized procedures or hard-to-handle reagents, which limits their generality for the functional group transformations. Difluoromethyl functionality (CF2H) has been known to be isosteric and isopolar to the hydroxyl group, and it behaves as a hydrogen donor through hydrogen bonding.9,10 Moreover, CF2H group has the similar high lipophilicity as the trifluoromethyl group. All these special properties make CF2H functionality a desired moiety to be incorporated into the organic molecules in order to enhance the their biological activities.11 Many functionalized difluoromethylalkanes have been applied in various fields such as pesticides,12 enzyme inhibitors,13 liquid crystals,14 and fluoropolymers.15 However, only a limited number of methods have been developed for the preparation of difluoromethylalkanes, including the deoxofluorination of aldehydes using SF4, DAST or SeF4,16 nucleophilic fluorination of gem-bistriflates using TBAF,17 fluorination of 1,2- or 1,3-dithiane using BrF3 and other in situ generated halogen fluorides,2e,18 and the addition of dibromodifluoromethane to double bonds.19 Most of these methods need the unpleasant reagents such as SF4, HF and their derivatives, with poor toleration of other functional groups on substrates. Thus, the new development of a general, mild and efficient synthetic method to selectively introduce 1,1-difluoro-1-alkene and difluoromethyl moieties into widely available organic substrates is of much importance.
Alky halides, such as alkyl iodides or bromides, are a group of easily available compounds, either from commercial sources or through the easy transformations from other compounds such as alcohols.20 Alkyl halides have been extensively used to form new carbon-carbon bonds due to the high reactivity of carbon-halogen bonds.21 However, little has been known about the selective carbon-carbon bond formation between a fluorinated carbon atom and the carbon atom of a simple aliphatic alkyl halide. The carbon-carbon bond formations between “CnF2n+1−” species with aromatic, and some particular alkyl halides (such as benzylic, allylic or propargylic alkyl halides) have been reported, using fluorine-containing organocopper (RfCu) species.22a-b,18b But the reaction usually does not work efficiently for other types of alkyl halides, which only affords low to moderate yields of products.22c-e Therefore, the selective and efficient carbon-carbon bond formation between a fluorinated carbon species and a simple alkyl halide (non-benzylic, non-allylic, non-propargylic) still remains a challenge.
The possible solution to this difficult problem is to introduce a proper auxiliary functional group connecting to the fluorinated carbon nucleophile to increase its softness, since the alkyl halide is a soft electrophile. Furthermore, the proper auxiliary group should be easily removed or transformed into other functional groups afterwards. Benzenesulfonyl group [PhS(O)2—] is one of the choices, for its softness and its varying chemical reactivities (so-called “chemical chameleon”).23,24 Difluoromethyl phenyl sulfone 1 is the ideal compound for this purpose, due to its easy generation of (benzensufonyl)difluoromethide 2 after the deprotonation of its acidic proton of CF2H group (Scheme 1).25-27 Difluoromethyl phenyl sulfone can be readily prepared from sodium thiophenoxide and chlorodifluoromethane followed by a simple oxidation.25-28 The nucleophilic addition of 1 with carbonyl compounds in the presence of a base has been demonstrated.26,27 Recently, we reported the synthetic application of 1 as a nucleophilic difluoromethylating agent29 as well as a selective difluoromethylenating agent27 for the diasteroselective synthesis of anti-2,2-difluoropropane-1,3-diols. However, the nucleophilic reaction of 1 (or 2) with alkyl halides is still unknown. Based on the above-mentioned mechanistic considerations, herein, we wish to report the unprecedented successful necleophilic substitution reactions of difluoromethyl phenyl sufone with primary alkyl halides (especially alkyl iodides), which allows us to accomplish the facile and efficient synthesis of 1,1-difluoro-1-alkenes and difluoromethylalkanes.
